RESUMO
Despite being one of the main components of anxiety and playing a pivotal role in how an individual perceives and copes with anxiogenic situations or responds to a given treatment, trait anxiety is paradoxically omitted in most animal models of anxiety. This is problematic and particularly more concerning in models that are used to screen drugs and other treatments for specific anxiety disorders and to investigate their neurobiological mechanisms. Our group has been engaged in the search for specific anxiety-related traits in animal models of anxiety. We developed two new lines of rats with strong phenotypic divergence for high (Carioca High-conditioned Freezing [CHF]) and low (Carioca Low-conditioned Freezing [CLF]) trait anxiety as expressed in the contextual fear conditioning paradigm. Here, we summarize key behavioral, pharmacological, physiological, and neurobiological differences in one these lines, the CHF rat line, relative to randomized-cross controls and discuss how far they represent a valid and reliable animal model of generalized anxiety disorder and so high trait anxiety.
RESUMO
The role of serotonin (5-hydroxytryptamine [5-HT]) and 5-HT2A receptors in anxiety has been extensively studied, mostly without considering individual differences in trait anxiety. Our laboratory developed two lines of animals that are bred for high and low freezing responses to contextual cues that are previously associated with footshock (Carioca High-conditioned Freezing [CHF] and Carioca Low-conditioned Freezing [CLF]). The present study investigated whether ketanserin, a preferential 5-HT2A receptor blocker, exerts distinct anxiety-like profiles in these two lines of animals. In the first experiment, the animals received a systemic injection of ketanserin and were exposed to the elevated plus maze (EPM). In the second experiment, these two lines of animals received microinjections of ketanserin in the infralimbic (IL) and prelimbic (PL) cortices and were exposed to either the EPM or a contextual fear conditioning paradigm. The two rat lines exhibited bidirectional effects on anxiety-like behavior in the EPM and opposite responses to ketanserin. Both systemic and intra-IL cortex injections of ketanserin exerted anxiolytic-like effects in CHF rats but anxiogenic-like effects in CLF rats. Microinjections of ketanserin in the PL cortex also exerted anxiolytic-like effects in CHF rats but had no effect in CLF rats. These results suggest that the behavioral effects of 5-HT2A receptor antagonism might depend on genetic variability associated with baseline reactions to threatening situations and 5-HT2A receptor expression in the IL and PL cortices. Highlights -CHF and CLF rats are two bidirectional lines that are based on contextual fear conditioning.-CHF rats have a more "anxious" phenotype than CLF rats in the EPM.-The 5-HT2A receptor antagonist ketanserin had opposite behavioral effects in CHF and CLF rats.-Systemic and IL injections either decreased (CHF) or increased (CLF) anxiety-like behavior.-PL injections either decreased (CHF) anxiety-like behavior or had no effect (CLF).
RESUMO
Subtle differences in neuronal microanatomy may be coded in individuals with genetic susceptibility for neuropsychiatric disorders. Genetic susceptibility is a significant risk factor in the development of anxiety disorders, including post-traumatic stress disorder (PTSD). Pavlovian fear conditioning has been proposed to model key aspects of PTSD. According to this theory, PTSD begins with the formation of a traumatic memory which connects relevant environmental stimuli to significant threats to life. The lateral amygdala (LA) is considered to be a key network hub for the establishment of Pavlovian fear conditioning. Substantial research has also linked the LA to PTSD. Here we used a genetic mouse model of fear susceptibility (F-S) and resistance (F-R) to investigate the dendritic and spine structure of principal neurons located in the LA. F-S and F-R lines were bi-directionally selected based on divergent levels of contextual and cued conditioned freezing in response to fear-evoking footshocks. We examined LA principal neuron dendritic and spine morphology in the offspring of experimentally naive F-S and F-R mice. We found differences in the spatial distribution of dendritic branch points across the length of the dendrite tree, with a significant increase in branch points at more distal locations in the F-S compared with F-R line. These results suggest a genetic predisposition toward differences in fear memory strength associated with a dendritic branch point organization of principal neurons in the LA. These micro-anatomical differences in neuron structure in a genetic mouse model of fear susceptibility and resistance provide important insights into the cellular mechanisms of pathophysiology underlying genetic predispositions to anxiety and PTSD.
Assuntos
Complexo Nuclear Basolateral da Amígdala/patologia , Espinhas Dendríticas/patologia , Medo/fisiologia , Animais , Aprendizagem da Esquiva/fisiologia , Condicionamento Clássico/fisiologia , Eletrochoque , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Rats selectively bred for high or low levels of emotionality represent an important and powerful tool to investigate the role of genetic variables in the occurrence of different anxiety disorders. In the present study, albino rats were selectively bred for differences in defensive freezing behavior in response to contextual cues previously associated with footshock, an animal model of general anxiety disorder. The results indicate that these two new lines of rats, which we refer to as Carioca High-Freezing (CHF) and Carioca Low-Freezing (CLF), show a reliable difference in conditioned freezing after three generations of selection. CHF and CLF rats did not present any differences during baseline or post-shock periods. Males from both lines consistently exhibit more conditioned freezing to contextual cues than females. A second experiment used male rats from the fourth generation to investigate the participation of the amygdala during contextual fear conditioning in the CHF and CLF lines. The results indicate that post-training amygdaloid electrolytic lesions lead to similar disruptions in conditioned freezing behavior in both animal lines.